Formulation, apparatus and method for stabilizing radiopharmaceuticals

ABSTRACT

A formulation for stabilizing a radiopharmaceutical. The formulation includes a radiopharmaceutical (or a pharmaceutically acceptable salt thereof), a gas which has oxygen, a stabilizer, and a solvent.

This application is a divisional of U.S. application Ser. No.13/813,687, filed on Apr. 2, 2013, which is the U.S. national phaseapplication of PCT International Application No. PCT/US2011/047717,filed on Aug. 15, 2011, which claims priority to Provisional U.S. PatentApplication Nos. 61/392,583, filed Oct. 13, 2010, and 61/373,321, filedAug. 13, 2010, the disclosures of which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to positron emission tomography (PET).More specifically, it relates to radiopharmaceuticals used in PET. Moreparticularly, it relates to formulations and methods for stabilizingthese radiopharmaceuticals. These formulations and methods prevent theseradiopharmaceuticals from degrading due to many factors includingradiolysis.

2. Description of Related Art

Over the past 10 years positron emission tomography (PET) has evolvedfrom a research tool to a commonly applied clinical diagnostic test. Atthe heart of PET imaging are isotope-labeled radiopharmaceuticals thatundergo specific biological transformations (e.g. enzymatictransformation, such as phosphorylation) or bind to biomolecules withhigh specificity and affinity. PET imaging not only enables diseasediagnosis in a clinical setting, but also supports the development ofnew therapeutic drugs by allowing receptor occupancy and pharmacokineticproperties to be evaluated in vivo.

The formulation and stabilization of radiopharmaceuticals for PETimaging is a critical component to the manufacturing process.Radiopharmaceuticals must be formulated appropriately for human dosing;the most common delivery route being intravenous administration ofaqueous solutions. At a minimum, the formulation must not adverselycompromise the stability of the radiopharmaceutical for the duration ofits shelf-life. In an ideal scenario, the formulation provides an extrameasure of protection against radiopharmaceutical degradation. Thisaspect of stability is critical since bulk dose vials containingradiopharmaceutical are often made in high strength (mCi/mL) to enabledispensing of multiple doses over a period of several hours. Inaddition, it is critical to maintain a high radiochemical purity toachieve the best image quality possible. If the stability of the bulkvial is compromised during the duration of its shelf-life, the dose maybe unusable and unfit for human dosing or imaging.

Radiopharmaceuticals can experience instability as a function ofstrength (mCi/mL), pH, temperature and specific activity. One of themajor issues with respect to radiopharmaceutical formulations isradiolysis (i.e. radiolytic degradation), which can occur while theradiopharmaceutical is aging in the dosing solution or bulk vial. Theradiolysis process is not fully understood but current research suggeststhat ionizing radiation, generated via positron decay, induces theformation of radicals. See Jan Van Den Bos, (Healthcare, G., Ed.) (2009)(related to WO 2009/059977); Maxim Y Kiselev et al., (Isotopes, E., Ed.)(2004) (related to WO 2004/043497; hanging Chen et al., (S.P.A., B. I.,Ed.) (2005) (related to WO 2005/009393); Richard M. Fawdry, Radiolysisof 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and the Role of ReductantStabilizers, Applied Radiation and Isotopes, vol. 65, pp. 1193-1201(2007).

For example, one reference describes radiolysis as being “caused mainlyby oxidation by free radicals that are produced by the interaction ofionizing radiation from the ¹⁸F-isotope with the water solvent andpossibly air”. Maxim Y Kiselev et al. (Isotopes, E., Ed.) (2004).Another reference cites that “the interaction of ionizing radiation withdissolved oxygen (O₂) can generate very reactive species such assuperoxide radicals. These radicals are very reactive towards organicmolecules”. Jianging Chen et al. (S.P.A., B. I., Ed.) (2005). As aconsequence of the formation of these radicals, they can react furtherwith each other, other radicals, oxygen and/or the radiopharmaceuticalitself eventually causing radiolytic decomposition of theradiopharmaceutical.

Experiments using ionizing radiation on solutions of thymdinedemonstrate the destructive effects caused by the decomposition productsthat react with thymidine. See J. R. Wagner et al., Photo andRadiation-Induced Formation of Thymidine Hydroperoxides,Bioelectrochemistry and Bioenergetics, vol. 18, pp. 155-162 (1987); R.Teoule & J. Cadet, Comparison of Radiolysis Products of Thymine andThymidine with E.S.R. Results, Int'l J. Radiation Biology, vol. 27, pp.211-222 (1975). The effects are further exacerbated by the presence ofoxygen and often lead to peroxide-containing adducts. While thesereports utilize an external source of radiation, the proposeddecomposition adducts react with thymidine in a fashion consistent withradiolysis. For example, the author states the following:

-   -   “The formation of hydroperoxides during gamma radiolysis of dThd        in oxygenated solutions most likely under these conditions        involves the initial reactions of hydroxyl radicals with dThd.        Hydroxyl radicals react with dThd by addition to the 5,6 double        bond and by hydrogen abstraction either from the sugar moiety or        from the methyl group.”        See J. R. Wagner et al., Photo and Radiation-Induced Formation        of Thymidine Hydroperoxides, Bioelectrochemistry and        Bioenergetics, vol. 18, pp. 155-162 (1987).

It is clear that ionization radiation, albeit from an external source,can lead to radiolysis on non-radioactive species, especially in thepresence of air (oxygen).

The byproducts from the radiolysis-induced radical reactions arebelieved to be strongly oxidizing. For example, if hydroxyl radical isformed during radiolysis, it may combine with another hydroxyl radicalto form hydrogen peroxide, a strong oxidizer. In another example, it iswidely believed that ionizing radiation in the presence of oxygen leadsto the formation of superoxide, a highly oxidizing and reactive species,which rapidly degrades radiopharmaceuticals. In an effort to combat thenegative effect of these radicals in a strongly oxidizing environment,stabilizers are often added to the dosing solution. More specifically,these stabilizers are comprised of radical scavengers and/oranti-oxidants (i.e. reductants), both of which are believed to exert aprotective effect upon the radiopharmaceutical against radiolysis. Theeffect of reductants on the inhibition of [F-18]FDG radiolysis is wellstudied in the art. See Richard M. Fawdry, Radiolysis of2-[18F]fluoro-2-deoxy-D-glucose (FDG) and the Role of ReductantStabilizers, Applied Radiation and Isotopes, vol. 65, pp. 1193-1201(2007).

Table 1 shows some commonly-used tracers and stabilizers commonly-usedwith these tracers.

TABLE 1 Common stabilizers for [F-18]-labeled radiopharmaceuticalsStabilizer Tracer Reference Ethanol [F-18]FDG WO2004043497N-t-butyl-alpha- [F-18]AV-19 Appl. Radiat. Isot. 2009, phenylnitrone(PBN) 67, 88-94 Sodium ascorbate [F-18]AV-19 Appl. Radiat. Isot. 2009,67, 88-94 Ascorbic acid [F-18]AV-45 WO2010078370 Ascorbic acid[F-18]FDDNP Appl. Radiat. Isot. 2008, 66, 203-207 Gentisic acid[F-18]FDG WO2009059977 Calcium chloride 2-[F-18]fluoromethyl- Nucl. Med.Biol. 2008, L-phenylalanine 35(4), 425-432

Consistent with the thinking that oxidation plays a negative role inradiopharmaceutical stabilization; oxidants are not used to stabilizeradiopharmaceuticals. Oxidants are expected to contribute to furtherradical growth, and thus increase the propensity for radiolysis. Onereference discloses that stabilized radiopharmaceutical compositions aredefined as those which are preferably stored in an environment fromwhich oxygen gas has been removed. Jan Van Den Bos, (Healthcare, G.,Ed.) (2009).

The above stabilizers are used in formulations that are devoid ofoxygen. Since the stabilizers are largely anti-oxidants, using them tostabilize radiopharmaceuticals in the presence of oxygen would beexpected to lessen their protective effect. For example, ascorbic acidrapidly degrades in the presence of oxygen, often changing color as aresult of this degradation. The rapid decay of these stabilizers in airalso means that solutions containing these stabilizers cannot be storedfor long periods of time.

Accordingly, if oxygen was found to have a protective effect againstradiolysis, then the addition of oxygen and certain non-oxidizingexcipients into radiopharmaceutical formulations may have a synergisticeffect that could not be accomplished through the use of either oxygenor the excipient alone. For example, if a non-oxidizing excipient suchas maleic acid (MA) exerted a stabilizing effect on radiopharmaceuticalsin the absence of oxygen, MA's protective effect on theradiopharmaceutical stability profile could be substantially increasedin the presence of oxygen.

Maleic acid (MA) is a dicarboxylic acid that is a common excipient innon-radioactive injectable formulations. Its toxicity profile is wellknown. Int'l J. Toxicology, Am. C. Toxicology, Final Report on theSafety Assessment of Maleic Acid, vol. 26, suppl. 2, pp. 125-130 (2007).It is listed as an inactive ingredient for injection by the UnitedStates Food and Drug Administration (FDA) with a maximum potency of0.01%.

MA causes a reversible malfunctioning of the proximal renal tubes inkidneys by forcing materials intended for re-absorption (glucose, HCO₃,etc.) to be excreted into the urine. Somchai Eiam-ong et al., InsightsInto the Biochemical Mechanism of Maleic Acid-Induced Fanconi Syndrome,Kidney Int'l, vol. 48, pp. 1542-1548 (1995); Edgar J. Rolleman et al.,Kidney Protection During Peptide Receptor Radionuclide Therapy withSomatostatin Analogues, Eur. J. Nuclear Med. & Molecular Imaging, vol.37, pp. 1018-1031 (2010); Salim K. Mujais, “Maleic Acid-Induced ProximalTubulopathy: Na:K Pump Inhibition”, J. Am. Soc'y Nephrology, vol. 4, no.2, pp. 142-147 (1993). The effect MA exerts on the kidneys mimics thehuman disease known as Fanconi Syndrome. The proposed mechanism ofaction of maleic acid's effect is to a) cause direct inhibition ofproximal tubule Na—K-ATPase activity and b) force membrane-boundphosphorus depletion. H. Al-Bander et al., Phosphate Loading AttenuatesRenal Tubular Dysfunction Induced by Maleic Acid In the Dog, Am. J.Physiology, vol. 248, pp. F513-F521 (1985). In dogs, this effect is seenwhen administered at 20 mg/kg (440 mg total dose). The human doseequivalent for this effect is predicted to be approximately 15 mg/kg(1000 mg total dose). In rats, the effect is seen when administered at50 mg/kg (12.5 mg total dose). The human dose equivalent for this effectis predicted to be approximately 12.3 mg/kg (855 mg total dose).

MA is commonly used in non-radioactive injectable solutions(antihistamine, utertonic, chemotherapeutic) as a counter salt or tomodulate pH of the injectable dose. See H. G. Boxenbaum et al.,Pharmacokinetic and Biopharmaceutic Profile of Chlordiazepoxide HCl InHealthy Subjects: Single-Dose Studies by the Intravenous, Intramuscular,and Oral Routes, J. Pharmacokinetics & Biopharmaceuticals, vol. 5, no.1, pp. 3-23 (1977); E. A. Peets et al., Metabolism of ChlorpheniramineMaleate In Man, J. Pharmacology & Experimental Therapeutics, vol. 180,pp. 364-374 (1972); R. G. Strickley et al., Solubilizing Excipients InOral and Injectable Formulations, Pharmaceutical Research, vol. 21, no.2, pp. 201-230 (2004); J. Verweij et al., “Frequent Administration ofDabis Maleate, a Phase I Study”, Annals of Oncology, vol. 3, pp 241-242(1992); William Sacks, Evidence For the Metabolism of Maleic Acid InDogs and Human Beings, Science, vol. 127, p. 594 (1958); G. Tagliabue etal., Antitumor Activity of1,4-bis(2′-chloroethyl)-1,4-diazabicyclo-[2.2.1]heptane dimaleate (DabisMaleate) In M5076 and Its Subline Resistant to Cyclophosphamide M5/CTX,Annals of Oncology, vol. 3, pp. 233-6 (1992); Maria E. L. van der Burget al., Phase I Study of DABIS Maleate Given Once Every 3 Weeks, Eur. J.Cancer, vol. 27, pp. 1635-1637 (1991); J. J. M. Holthuis, Etoposide andTeniposide: Bioanalysis, Metabolism and Clinical Pharmacokinetics,Pharmaceutisch Weekblad Sci. Edition, vol. 10, pp. 101-116 (1998); P.Borchmann et al., Phase I Study of BBR 2778, A New Aza-Anthracenedione,In Advanced or Refractory Non-Hodgkin's Lymphoma, Annals of Oncology,vol. 12, pp. 661-667 (2001); J. G. Reves et al., Midazolam MaleateInduction In Patients With Ischaemic Heart Disease: HaemodynamicObservations, Canadian Anesthetists' Soc'y J., vol. 26, no. 5, pp.402-409 (1979); S. M. Huang et al., Pharmacokinetics of ChlorpheniramineAfter Intravenous and Oral Administration In Normal Adults, Eur. J.Clinical Pharmacology, vol. 22, pp. 359-365 (1982). A table summary thatexplains under which circumstances maleic acid is injected into humansis given below (Table 2).

TABLE 2 Presence of maleic acid in human injectables Therapeutic/ Totalcompound Class Status MA Use Dose Methergine Utertonic ApprovedExcipient 0.1 mg Piriton Antihistamine Approved Salt form 1.2 mg BBR2778Chemo Phase III Salt form  2.8 mg* DABIS maleate Chemo Phase II Saltform  34 mg* Maleic-2-¹⁴C Metabolism study N/A Direct  11 mg (1958)

MA is not known to stabilize radiopharmaceuticals. For example, MA wastested as a stabilizer for radiopharmaceutical ^(99m)Tc(Sn)-DTPA with astrength of 7-9 mCi/mL. However, in the reported study, MA was “not ableto prevent the decomposition of ^(99m)Tc(Sn)-DTPA.” Ralf Berger, RadicalScavengers and the Stability of ^(99m) Tc-Radiopharmaceuticals, Int'l J.Applied Radiation & Isotopes, vol. 33, pp. 1341-1344 (1982). MA has beenused to prevent rancidity in fats for a period of weeks, yet MA'sprotective effect is diminished in the presence of water. George R.Greenbank & George E. Holm, Antioxidants for Fats and Oils, Indus. &Engineering Chemistry, vol. 26, no. 3, pp. 243-245 (1934).

SUMMARY OF THE INVENTION

The present invention relates to formulations, apparatuses and methodsfor stabilizing radiopharmaceuticals. Such radiopharmaceuticals may bepositron-emitting and may comprise, for example, [F-18]fluoride or[C-11]carbon. One radiopharmaceutical may be [F-18]FDG. Others mayinclude [F-18]FMAU, [F-18]FMISO, [F-18]FHBG, [F-18]AV-45, [F-18]AV-19,[F-18]AV-1, [F-18]Flutemetamol, [F-18]Flurpiridaz, [F-18]K5, [F-18]HX4,[F-18]W372, [F-18]VM4-037, [F-18]CP18, [F-18]ML-10, [F-18]T808,[F-18]T807 and 2-[F-18]fluoromethyl-L-phenylalanine. It is envisionedthat virtually any radiopharmaceutical may be used and stabilized withthe present formulation. Such may have radiolabels selected from thegroup consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁸Ga,¹²⁴I, ¹²⁵I, ¹³¹I, ⁹⁹Tc, ⁷⁵Br, ¹⁵³Gd and ³²P. The formulations,apparatuses and methods preferably comprise a gas of about 10 vol. % toabout 100 vol. % oxygen as a stabilizer in the presence of an excipientsuch as maleic acid. Oxygen may refer to substantially pure O₂ or “air”,which may comprise smaller amounts of nitrogen, carbon dioxide, argon,etc.

In one embodiment, the present invention is a formula for stabilizing aradiopharmaceutical. The formula comprises a solution comprising aradiopharmaceutical, a stabilizer and water. The stabilizer may be anoxidant such as oxygen. The stabilizer may also be an excipient such asmaleic acid. A gas may include the oxidant in an amount of about 21 vol.%. The formula may also comprise inorganics such as phosphates, sodiumchloride, sodium bicarbonate, HCl, NaOH, etc. The formula may furthercomprise an inorganic salt. Such salts include but are not limited tophosphates such as NaH₂PO₄, Na₂HPO₄ and Na₃PO₄. The formula may alsocomprise an alcohol such as ethanol.

In another embodiment, the present invention is an apparatus forstabilizing a radiopharmaceutical. The apparatus comprises a containerhaving a formula comprising a radiopharmaceutical, the stabilizer andwater. The stabilizer preferably comprises maleic acid. The containermay be sealable and, when sealed, be substantially impermeable tooxygen.

In another embodiment, the present invention is a method of making aformula for stabilizing a radiopharmaceutical. The method comprisesproviding a radiopharmaceutical, providing a stabilizer and providingwater. Preferably, the stabilizer is maleic acid. An alcohol such asethanol and a salt such as a phosphate may also be provided.

We have shown that 8 vol. % EtOH:92 vol. % sodium phosphate (21 mM,pH=4.0-7.0) containing 0.01% (g/ml) maleic acid is very efficient atstabilizing [F-18]FLT.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing how [F-18]FLT decomposes in the presence ofargon without oxygen (upper trace) and how [F-18]FLT is stabilized inthe presence of oxygen (lower trace).

FIG. 2 is a graph showing how [F-18]FLT decomposes in the presence ofargon without maleic acid and how [F-18]FLT is stabilized in thepresence of maleic acid in argon.

FIG. 3 is a graph showing how [F-18]FLT containing maleic acid and air(oxygen: 20.95 vol. %) are equally stable at 50° C. for a period of 2hours.

FIG. 4 is a graph showing how [F-18]FLT decomposes in the presence ofoxygen once the oxygen is consumed and how [F-18]FLT is furtherstabilized in the presence of oxygen and maleic acid.

FIG. 5 is a graph showing how [F-18]FLT is formulated in EtOH:phosphatecontaining 0.01% (g/ml) maleic acid at EOS. The top trace is theradioactivity trace; the bottom trace is the UV trace.

FIG. 6 is a graph showing how [F-18]FLT is formulated in EtOH:phosphatecontaining 0.01% (g/ml) maleic acid at 8 hrs post EOS. The top trace isthe radioactivity trace, the bottom trace is the UV trace. There is nochange in the chemical or radiochemical signal after aging.

DETAILED DESCRIPTION OF EMBODIMENTS

It is to be understood that the figures and descriptions of the presentinvention have been simplified to illustrate elements that are relevantfor a clear understanding of the present invention, while eliminating,for purposes of clarity, many other elements which are conventional inthis art. Those of ordinary skill in the art will recognize that otherelements are desirable for implementing the present invention. However,because such elements are well known in the art, and because they do notfacilitate a better understanding of the present invention, a discussionof such elements is not provided herein.

The present invention will now be described in detail on the basis ofexemplary embodiments.

Unless otherwise specified, the percentages of various constituents inliquid phases discussed below (including gases dissolved in a liquidphase) are mass per mass percentages (as mass of constituent over totalmass), or volume per volume percentages (as volume of constituent overtotal volume), as a percentage of a given phase. For example, apercentage of ethanol being around 8 vol. % is given as a percentage ofthe total liquid phase. Similarly, a percentage of oxygen being around20.95 vol. % is given as a percentage of the total gas phase (e.g.,headspace). The only exception is that the percentage of maleic acid isgiven as a mass per liquid volume percentage, as grams of maleic acidover total liquid volume in milliliters. For example, 0.1 mg/ml ofmaleic acid equals 0.0001 g/ml. To then get the percentage of maleicacid, the concentration in grams per milliliter is multiplied by 100%,arriving at a percentage of 0.01% maleic acid (which corresponds to theFDA's maximum potency for maleic acid).

As used below, the terms “sparge”, “sparged”, “sparging”, and othersimilar variations refer both to sparging by filling a headspace with asparging gas to remove an unwanted gas, and to sparging by bubbling thesparging gas through a liquid to remove the unwanted gas.

In the present invention, radiopharmaceutical formulations shouldcontain a gas having between about 10 vol. % and about 100 vol. % oxygenin the bulk vial, in solution and also in the vial headspace. In someembodiments, the formulation comprises a gas of about 20.95 vol. %oxygen. The radiopharmaceutical formulation may also contain astabilizer such as maleic acid, with a maximum amount of maleic acidbeing 0.5% (as grams of maleic acid per total milliliter of liquid).This novel formulation has been demonstrated to provide a uniquestabilizing effect which efficiently guards against many types ofdegradation including radiolysis. One way in which the present inventiondistinguishes itself from existing formulations is through the presenceof oxygen in the final formulation of PET radiopharmaceuticals toprevent radiolysis. Contrary to the cited literature, in the formulationof the present invention, oxygen prevents radiolysis, rather thanpromoting radiolysis. Secondly, the use of maleic acid to stabilizeradiopharmaceuticals is not known in the art. Lastly, the synergisticcombination of oxygen and maleic acid to stabilize radiopharmaceuticalsis not known in the art.

In the formulation of the present invention, the synergistic combinationof oxygen and maleic acid was discovered to possess a unique ability tostabilize [F-18]FLT in dosing solutions with high strength for a periodof 4 to 10 hours. Preferably, the strength of the dosing solution is atleast 10 mCi/ml. More preferably, the strength of the dosing solution isat least 30 mCi/ml. Even more preferably, the strength of the dosingsolution is at least 60 mCi/ml to over 120 mCi/ml. In some instances,the formulation was stable for about 18 hours. The formulations werestored at temperatures of about 0° C. to about 50° C. Formulations of[F-18]FLT which are devoid of oxygen rapidly decomposed within a 2 to 3hour timeframe. Stabilized samples of [F-18]FLT containing O₂ had higheramounts of hydrogen peroxide present in solution than radiolyzed samplesthat contained no O₂. Therefore, samples of [F-18]FLT spiked with O₂,and ultimately hydrogen peroxide, did not contain radiolyzed products upto 197 mCi/mL. This suggests that O₂ spiked solutions preventedradiolysis through a protective mechanism while simultaneouslygenerating hydrogen peroxide. Therefore, the presence O₂ is linked tothe formation of hydrogen peroxide. When samples were devoid of O₂ butcontained maleic acid as the stabilizer, very little hydrogen peroxidewas formed yet radiolytic decomposition was also greatly slowed. Thepresence of oxidants or electron deficient compounds, such as maleicacid, appear to stabilize [F-18]FLT and other radiopharmaceuticals fromradiolytic degradation. Therefore, without being bound by theory, itappears that the presence of oxygen and maleic acid in this formulationis critical and advantageous for the preparation of [F-18]FLT in highstrength while preserving radiochemical purity. The use of oxygen andmaleic acid as stabilizers in this formulation is surprisinglyeffective, yet easy to handle in its sterile form and is fullybiocompatible for human injection.

The invention will now be illustrated by the following examples.

EXAMPLES

[F-18]FLT was prepared on an explora GN synthesis module using theBoc-Boc-Nos FLT precursor. (See, e.g., U.S. Pat. No. 7,160,537, which isincorporated by reference). It will be understood that other methods offormulating [F-18]FLT may be used in conjunction with the presentinvention. The [F-18]FLT was purified by reverse phase C18semi-preparative HPLC using 8 vol. % EtOH: 92 vol. % 21 mM sodiumphosphate. When MA was used in the formulation, it was introduced intothe radiopharmaceutical by either spiking with a small volume of a 1g/100 mL solution or alternatively introduced into the mobile phase.[F-18]FLT was purified by reverse phase C18 semi-preparative HPLC using8 vol. % EtOH: 92 vol. % 21 mM sodium phosphate containing 0.01% (g/ml)maleic acid. The collected HPLC fraction was passed over an Al₂O₃cartridge followed by sterile filtration into a pyrogen-free sterilevial. The radiochemical purity of [F-18]FLT was measured byradio-analytical HPLC equipped with a gamma detector. It will beunderstood that other methods of purifying [F-18]FLT may be used inconjunction with the present invention. The analysis was performed usinga MeCN:water gradient on a C18 column with a 1 mL/min flow rate. Thepercent stability is defined as the ratio between the area of parent[F-18]FLT versus the remaining [F-18]-labeled by-products. A headspaceof oxygen refers to a gaseous mixture of about 20.95 vol. % oxygen.[F-18]HX4, [F-18]W372 and [F-18]BMS757158-02 were prepared according topublished procedures. Other excipients that were used to stabilize[F-18]FLT include beta-cyclodextrin, methylene blue, alpha-cyclodextrin,gentisic acid, cyclohexane dione diamine, ascorbic acid, thioglycerol,glutathione, tartaric acid, niacinamide, ascorbic acid, FeCl₃, H₂O₂,glutamic acid, triamine pentaacid, methylene diphosphonic acid,beta-hydroxypropyl cyclodextrin, xanthine, aspartic acid, chlorobutanol,calcium chloride, mannitol, creatanine, calcium gluconate, dimethylacetamide, diazatriazoic acid, sodium succinate, boric acid and sodiumcarbonate. Hydrogen peroxide concentration (ppm) was determined usingperoxide test strips.

Example 1

A solution of [F-18]FLT (126.8 mCi/mL at EOS), formulated in 8 vol. %EtOH: 92 vol. % phosphate, was kept either with a headspace of 20.95vol. % oxygen (dose vial) or without a headspace of oxygen (syringe). Asshown in Table 3, after 3.5 hrs, the solution of [F-18]FLT without theheadspace of oxygen decomposed to 65% radiochemical purity. The samplewith the headspace of oxygen remained radiochemically intact. This datasupports the finding that oxygen provides a stabilizing effect on[F-18]FLT in aqueous ethanol.

TABLE 3 Shows percent stability after 3.5 hours for a syringe withoutoxygen and vial with oxygen-filled headspace. mCi/mL analysis %stability FLT batch at EOS formulation method 3.5 hr 100728-syringe-126.8 8 vol. % EtOH:92 HPLC 65 NO HEADSPACE vol. % phosphate 100728-dosevial- 126.8 8 vol. % EtOH:92 HPLC 99.9 HEADSPACE vol. % phosphate

Example 2

A solution of [F-18]FLT (129.5 mCi/mL at EOS), formulated in 8 vol. %EtOH: 92 vol. % phosphate, was drawn into a syringe with either aheadspace of oxygen (20.95 vol. %) or without a headspace of oxygen.Initially, both samples were stable. After 2.6 hrs, however, thesolution of [F-18]FLT without the headspace of oxygen decomposed to66.7% radiochemical purity. The sample continued to further degrade to32.7% radiochemical purity after 3.8 hrs. The sample with the headspaceof oxygen remained radiochemically intact. As a control, a dose vialwith a headspace of oxygen also remained radiochemically intact. Thisdata supports the finding that oxygen provides a stabilizing effect on[F-18]FLT in aqueous ethanol in syringes.

TABLE 4 Shows percent stability at various time intervals for a syringewithout headspace and, therefore, no oxygen, a syringe with headspaceand, therefore, oxygen and a dose vial with oxygen. mCi/mL analysis %stability % stability % stability % stability FLT batch at EOSformulation method 0.5 hr 1.6 hr 2.6 hr 3.8 hr 100729- 129.5  8 vol. %EtOH: HPLC 100 100 66.7 32.7 syringe NO 92 vol. % phosphate HEADSPACE100729- 129.5  8 vol. % EtOH: HPLC 100 100 99.5 99.6 syringe- 92 vol. %phosphate HEADSPACE 100729- 129.5  8 vol. % EtOH: HPLC 100 99.4 99.899.2 dose vial- 92 vol. % phosphate HEADSPACE

Example 3

A solution of [F-18]FLT (63.2 mCi/mL at EOS), formulated in 8 vol. %EtOH: 92 vol. % phosphate, was drawn into a syringe with headspace ofoxygen (20.95 vol. %). A second sample was transferred into a secondvial purged with a gas having 20.95 vol. % oxygen. The dose vial wassparged with Ar to remove oxygen. After 1.5 hrs, the dose vialcontaining [F-18]FLT which was sparged with Ar, decomposed to 62.5%radiochemical purity. This sample continued to further degrade to 38.57%radiochemical purity after 4.0 hrs. The samples with the headspace ofoxygen (both the syringe and sample vial) remained radiochemicallyintact up to 4 hrs. This data supports the finding that oxygen providesa stabilizing effect on [F-18]FLT in aqueous ethanol in bulk vials withoxygen dissolved in solution as well as being present in the vialheadspace.

TABLE 5 Shows percent stability at various time intervals for a syringewith headspace, an Argon sparged dose vial and an O₂-purged dose vial.mCi/mL analysis % stability % stability % stability FLT batch at EOSformulation method 0.5 hr 1.5 hr 4 hr 100730-syringe- 63.2  8 vol. %EtOH: HPLC 100 100 100 HEADSPACE 92 vol. % phosphate 100730-Ar sparged63.2  8 vol. % EtOH: HPLC — 62.5 38.5 dose vial 92 vol. % phosphate100730-O₂ purged 63.2  8 vol. % EtOH: HPLC — 100 100 dose vial 92 vol. %phosphate

This data supports the finding that oxygen provides a stabilizing effecton [F-18]FLT in aqueous ethanol.

A solution of [F-18]HX4 (28.5 mCi/mL after reformulation or 16.2 mCi/mLafter reformulation), formulated in either 10 vol. % EtOH:water or 8vol. % EtOH: 92 vol. % phosphate, in vials with either a headspace ofargon or air (oxygen: 20.95 vol. %). After 1 hrs, the dose vialcontaining [F-18]HX4 in 10 vol. % EtOH:water, which was sparged with Ar,decomposed to 0.28% radiochemical purity (Table 6). This samplecontinued to further degrade to 0% radiochemical purity after 4.0 hrs.The sample with the headspace of oxygen remained radiochemically intactup to 4 hrs. The [F-18]HX4 in 8 vol. % EtOH: 92 vol. % phosphate with aheadspace of argon decomposed to 85.6% radiochemical purity after 3 hrs.In the presence of air, the radiochemical purity was 94.06%. This datasupports the finding that oxygen stabilizes [F-18]HX4 against radiolyticdecomposition.

TABLE 6 Solutions of [F-18]HX4 aged in either the presence of air (20.95vol. % oxygen) or argon. Samples aged in the presence of air (20.95 vol.% oxygen) were more stable than those samples aged under argon. % % %mCi/ stability stability stability Sample mL formulation Additive 1 hr 3hr 4 hr HX4- 28.5 10 vol. % EtOH: Air (O₂) 98.33 — 99.01 922- water100805- AIR HX4- 28.5 10 vol. % EtOH: Argon 0.28 — 0 922- water 100805-AR purged HX4- 16.2  8 vol. % EtOH: Air (O₂) — 94.06 — 922- phosphate100909 HX4- 16.2  8 vol. % EtOH: Argon — 85.6 — 922- phosphate 100909

Example 5

An aerated sample of [F-18]BMS 747158-02 (12 mCi/mL), formulated in 10vol. % EtOH:water was set aside for aging. The remaining solution wassparged with Ar to remove oxygen. After 2.25 hrs, the dose vialcontaining [F-18] BMS 747158-02 sparged with Ar, decomposed to 12%radiochemical purity. The aerated sample with had a radiochemical purityof 91% after 2.25 hrs. This data supports the finding that oxygenstabilizes [F-18]BMS 747158-02 against radiolytic decomposition.

TABLE 7 Solutions of [F-18]BMS 757158-02 were more stable in air(oxygen) than in argon. BMS mCi/mL % stability 747158-02 at EOSformulation additive 2.25 hr BMS-922- 12 10 vol. % Air/O₂ 91 100824EtOH:water (before sparge) BMS-922- 12 10 vol. % Argon 12 100824EtOH:water (reformulated after sparge)

Example 6

A aerated sample of [F-18]W372 (19.2 mCi/mL), formulated in 10 vol. %EtOH:water was set aside for aging. The remaining solution was spargedwith Ar to remove oxygen. After 1.5 hrs, the dose vial containing[F-18]W372 sparged with Ar, decomposed to 94.6% radiochemical purity.The sample with the headspace of oxygen had a radiochemical purity of97.6% after 1.5 hrs. This data supports the finding that oxygenstabilizes [F-18]W372 against radiolytic decomposition.

TABLE 8 Solutions of [F-18]W372 were more stable in air (oxygen) than inargon. % stability Sample mCi/mL formulation additive 1.5 hr W372-922-19.2 10 vol. % Argon 94.6 100907 EtOH:water W372-922- 19.2 10 vol. % O₂97.6 100907 EtOH:water

Example 7

A solution of [F-18]FLT (103 mCi/mL), formulated in 8 vol. %EtOH:phosphate, was sparged with argon to remove oxygen in the sample.An aliquot was removed and spiked with degassed maleic acid. Bothsamples were aged for 4 hrs. After 4 hrs, the sample without maleic acidhad a radiochemical purity of 1.5%. The sample containing maleic acidhad a radiochemical purity of 88.7%. This data supports the stabilizingeffect of maleic acid on [F-18]FLT. Hydrogen peroxide was measured usingtest strips. The FLT sample (126.3 mCi/mL) containing a headspace ofargon contained no detectable hydrogen peroxide (i.e. 0 ppm). The FLTsample (126.3 mCi/mL) containing maleic acid contained no detectablehydrogen peroxide (i.e. 0 ppm).

TABLE 9 [F-18]FLT aged in argon containing maleic acid was more stablethan a sample of [F-18]FLT aged in argon without maleic acid. %stability Sample mCi/mL formulation additive 4.0 hr FLT-922- 126.3 8vol. % Ar 1.5 100901 EtOH:phosphate FLT-922- 126.3 8 vol. % maleic acid88.77 100901 EtOH:phosphate (0.1 mg/mL) and Ar

Example 8

A sample of [F-18]FLT (118 mCi/mL), formulated in aerated 8 vol. %EtOH:phosphate, was removed for aging. The headspace in the remainingsample was sparged with argon to remove oxygen. After 3.25 hrs, thesample with maleic acid under argon had a radiochemical purity of 37.9%.The sample containing maleic acid in oxygen had a radiochemical purityof 99.8%. This data supports the increased stabilizing effect of maleicacid on [F-18]FLT in air over argon.

TABLE 10 Samples of [F-18]FLT containing maleic acid showed differingstability when aged in the presence of air versus argon. The sample agedin air was more stable than the sample stored under argon. % stabilitySample mCi/mL formulation additive 3.25 hr FLT-922- 118.7 8 vol. %maleic acid + 99.8 100903 EtOH:phosphate Air headspace FLT-922- 118.7 8vol. % maleic acid + 37.9 100903 EtOH:phosphate Ar headspace

Example 9

Solutions of [F-18]FLT (82 mCi/mL), formulated in aerated 8 vol. %EtOH:phosphate, containing 0.01% (g/ml) maleic acid were aged for 2hours at either room temperature or at 50° C. After 2 hrs, both sampleshad a radiochemical purity of 100%. This data supports the finding thatmaleic acid does not cross-react with [F-18]FLT at either elevated orroom temperature.

TABLE 11 Samples of [F-18]FLT containing maleic acid and air wereequally stable at 50° C. for a period of 2 hours. % stability SamplemCi/mL formulation additive 2 hr FLT-922- 82 8 vol. % maleic acid + 100100907 EtOH:phosphate Air headspace (rt) FLT-922- 82 8 vol. % maleicacid + 100 100907 EtOH:phosphate Air headspace (50 C.)

Example 10

An aerated sample of [F-18]FLT (197 mCi/mL) formulated in 8 vol. % EtOH:92 vol. % phosphate was either spiked or not spiked with maleic acid(0.1 mg/mL). The samples were aged for 3.5 hrs. After this time, thesample not containing maleic acid had a radiochemical purity of 82.6%.The spiked sample had a radiochemical purity of 99.2%.

In a separate experiment, [F-18]FLT (127 mCi/mL) formulated in 8 vol. %EtOH: 92 vol. % phosphate was either spiked or not spiked with maleicacid (0.1 mg/mL) and additional aliquots were drawn into syringeswithout a headspace of air. The samples were aged for 5.5 hours. Whilethe vial samples remained radiochemically intact (98% or greater) withor without maleic acid, the syringe samples varied remarkably. Thesample aged in the syringe without maleic acid had a radiochemicalpurity of 19.68%. The syringe sample containing maleic acid had aradiochemical purity of 97.13%. The experiment shows the synergisticstabilization effect of maleic acid and oxygen in stabilizing [F-18]FLT.Hydrogen peroxide was measured using test strips. The FLT sample (127mCi/mL) containing a headspace of oxygen contained hydrogen peroxidewith a concentration of 5 ppm. The FLT sample (127 mCi/mL) containing aheadspace of oxygen and maleic acid contained hydrogen peroxide with aconcentration of 0.5-2.0 ppm.

TABLE 12 Bulk vials of [F-18]FLT containing a headspace of air,dissolved air and maleic acid are more stable than [F-18]FLT containingonly a headspace of air and dissolved air. This was further confirmed inaged syringe samples in which the maleic acid spiked sample was morestable than the sample without maleic acid. % sta- % sta- bility bilitySample mCi/mL formulation additive 3.5 hr 5.5 hr FLT-922- 197.1 8 vol. %maleic 99.2 — 100909 EtOH:phosphate acid + O2 FLT-922- 197.1 8 vol. %FLT dose 82.6 — 100909 EtOH:phosphate vial (air/O2 only) FLT-922- 127 8vol. % maleic — 99.48 100908 EtOH:phosphate acid + Air headspace (rt)FLT-922- 127 8 vol. % Air — 98 100908 EtOH:phosphate headspace FLT-922-127 8 vol. % maleic — 97.13 100908 EtOH:phosphate acid + O2 (syringe (nosample) headspace) FLT-922- 127 8 vol. % O2 (no — 19.68 100908EtOH:phosphate headspace) (syringe sample)

Example 11

A sample of [F-18]W372 (19.2 mCi/mL) formulated in aerated 10 vol. %EtOH:water containing 0.01% (g/ml) maleic acid was set aside for aging.The remaining sample was purged with argon to remove oxygen. The sampleswere aged for 1.5 hours. The sample aged under argon had a radiochemicalpurity of 90.1%. The sample stored in the presence of air had aradiochemical purity of 94.9%. This data supports the increasedstability of [F-18]W372 in the presence of maleic acid and oxygen.

TABLE 13 A sample of [F-18]W372 aged in maleic acid and air (oxygen:20.95 vol. %) was more stable than a sample aged with maleic acid inargon. % stability Sample mCi/mL formulation additive 1.5 hr W372-922-19.2 10 vol. % maleic acid + 94.9 100907 EtOH:water O2 W372-922- 19.2 10vol. % maleic acid + 90.1 100907 EtOH:water Argon

Example 12

A sample of [F-18]HX4 (16.2 mCi/mL) formulated in aerated 10 vol. %EtOH:water containing 0.01% (g/ml) maleic acid was set aside for aging.The remaining sample was purged with argon to remove oxygen. The sampleswere aged for 3 hours. The sample under argon had a radiochemical purityof 8.66%. The sample stored in the presence of air had a radiochemicalpurity of 98.9%. This data supports the increased stability of [F-18]HX4in the presence of maleic acid and oxygen.

TABLE 14 [F-18]HX4 stored in the presence of maleic acid and oxygen ismore stable than when stored in the presence of maleic acid and argon. %stability Sample mCi/mL formulation additive 3 hr HX4-922- 16.2 8 vol. %maleic acid + 98.9 100909 EtOH:phosphate O2 HX4-922- 16.2 8 vol. %maleic acid + 8.66 100909 EtOH:phosphate Argon

Example 13

Dose vials of [F-18]FLT were formulated in 8 vol. % EtOH:92 vol. %phosphate and degassed via argon sparging. Aliquots from the dose vial(typically mL) were withdrawn and placed into argon sparged vialscontaining various excipients (typically 50 mg). The samples were aged(1 to 5 hours) and the radiochemical purity of [F-18]FLT was determined.Several excipients were found to stabilize [F-18]FLT against radiolysisin the presence of argon. Other excipients destabilized or had no effecton the stabilization of [F-18]FLT in the presence of argon in aqueousethanol. The protective factor (PF) was determined by dividing thepercent radiochemical stability of the excipient-doped dose by thepercent radiochemical stability of the argon-sparged dose. The resultsare shown in Table 15. One excipient that was found to be highlystabilizing in the absence of oxygen, and in the presence of argon, wasmaleic acid. Ascorbic acid, a known radiopharmaceutical stabilizer andanti-oxidant, was not as effective in stabilizing [F-18]FLT againstradiolysis at 50 mg/mL as compared to oxygen.

TABLE 15 A summary of excipients that were screened for their protectiveeffect in stabilizing [F-18]FLT. Stabilizing No Effect Destabilizing(PF > 1.1) (PF 1.1 to 1.0) (PF < 1.0) chlorobutanol glutamic acid Arcreatanine Ascorbic acid N₂ O₂ alpha-cyclodextrin Ar + FeSO₄ + H₂O₂dimethyl acetamide Ar + H₂O₂ methylene diphosphonic acid diazatriazoicacid beta-cyclodextrin aspartic acid Maleic acid methylene bluebeta-hydroxypropyl cyclodextrin O₂ + maleic acid triamine pentaacidXanthine Glutathione Ar + FeSO₄ Calcium gluconate H₂O₂ tartaric acidmannitol niacinamide Calcium Chloride cyclohexane Sodium Succinate dionediamine triethanolamine boric acid FeCl₃ sodium carbonate thioglycerolBoric acid Gentisic acid Sodium carbonate

Example 14

A solution of [F-18]FLT (50 mCi/mL at EOS), formulated in aerated 8 vol.% EtOH: 92 vol. % phosphate containing 0.01% (g/ml) maleic acid (FIG.5), was aged in a sterile vial in air for a period of 8 hrs. After 8hrs, the chemical and radiochemical analysis indicated that [F-18]FLTdid not undergo any decomposition during this aging period (FIG. 6).

Example 15

It was further confirmed that the presence of air in a containerheadspace provides protection against radiolysis by a storing FLT incontainers with air in the vial headspace or following sparging of avial with Argon to displace residual air and measuring RCP over time.

RCP % 1.5 hrs post RCP % 4 hrs post Container dispensing dispensingAir-purged vial 100 100 Argon purged vial 62.5 38.5

This showed that air does have a stabilizing effect on FLT under theseexperimental conditions.

In order to further assess the stability of FLT in air-filled sterilevials, vials were sourced from a company called Greer in the UnitedStates of America.

A summary of the stability data for radiochemical purity (“RCP”) in twotrial batches using the Greer vial is provided in the table below

FLT Batch RCP % 5 hrs post RCP % 10 hrs post Number RCP % t0 dispensingdispensing 54-T-280710-1 100 96.5 — 54-T-300710-1 100 100 100

Although some degradation was reported this did not exceed the specifiedlimit of <5% radiochemical impurities.

In order to further assess the effect of oxygen on RCP, vials from Greerand another company (Adelphi) were used to test the effect of varyingpercentages of oxygen in the headspace. A summary of this stability datais shown below.

O2 vol. % In N2 vol. % In FLT RCP ITN or Lot Supplier HeadspaceHeadspace results 763 Adelphi 10.74 87.24 Good 763 Adelphi 10.36 87.62Good 763 Adelphi 10.17 87.79 Good 763 Adelphi 10.24 87.74 Good 763Adelphi 10.67 87.30 Good 1030 Adelphi 5.15 92.83 Bad 1030 Adelphi 5.1792.80 Bad 1030 Adelphi 5.21 92.76 Bad 1030 Adelphi 5.12 92.83 Bad 1030Adelphi 5.04 92.93 Bad 155500 Greer 19.57 78.25 Good 155500 Greer 19.6078.21 Good 155500 Greer 19.57 78.24 Good 155500 Greer 19.66 78.12 Good155500 Greer 19.53 78.28 Good 54-T-300108-1 Adelphi 11.00 86.99 GoodVial 9 54-T-310108-1 Adelphi 11.22 86.77 Good Vial 9 54-T-100609-1Adelphi 13.56 84.42 Good Vial 9 54-T-110609-1 Adelphi 13.15 84.85 GoodVial 9 54-T-170709-1 Adelphi 14.65 83.33 Good Vial 9

As can be seen above, the FLT stability is improved when oxygen ispresent in the finished product vial headspace in a percentage of abovearound 10 vol. %.

Example 16

[F-18]VM4-037 and [F-18]K5 were found to be susceptible to radiolyticaldecomposition when stored under an atmosphere of He. When oxygen wasintroduced into the sample vials, [F-18]VM4-037 and [F-18]K5 were foundto not undergo radiolysis.

Example 17

The stabilizing effect of ascorbic acid was examined with and without aheadspace of air. In entries 1 through 8, ascorbic acid does indeedstabilize [F-18]FLT against radiolysis at nominal strength (62 mCi/mL)with or without the presence of oxygen. For these studies, very highconcentrations of ascorbic acid were used (50 to 100 mg/mL). However, atslightly reduced concentrations of ascorbic acid (8 mg/mL) and higher[F-18]FLT strength (130 mCi/mL), ascorbic acid failed to stabilize[F-18]FLT with or without the presence of oxygen, suggesting that theamount of radiolysis was independent of oxygen. Ascorbic acid canstabilize [F-18]FLT against radiolysis, but only up to a mCi/mLconcentration that is lower than that of oxygen sparged samples orsamples containing oxygen plus maleic acid. Also, given that ascorbicacid is a reductant, any oxygen present in solution would be consumed byascorbic acid, thus negating any stabilizing effect due to oxygen. Inthis experiment, ascorbic acid failed to provide radiolytic protectionfor [F-18]FLT beyond a strength of 130 mCi/mL.

FLT Batch Strength Headspace Entry (MIBR) (mCi/mL) (+/−) AA (+/−) TimeRCP 1 Dose vial 62 + 50 mg/mL 6 hrs 100% 2 Syringe 62 + 50 mg/mL 6 hrs100% 3 Syringe 62 − 50 mg/mL 6 hrs 100% 4 Dose Vial 50 + 50 mg/mL 7 hrs100% 5 Syringe 50 + 50 mg/mL 7 hrs 100% 6 Syringe 50 − 50 mg/mL 7 hrs100% 7 Dose vial/ 66 + 100 mg/mL  4 hrs 100% syringe 8 Dose vial/ 66 −100 mg/mL  4 hrs 100% syringe 9 Dose Vial 130 +  8 mg/mL 4.5 hrs    82%10 Dose Vial 130 −  8 mg/mL 4.5 hrs    79%

In addition to the processes described above, air may be incorporatedinto the above formulations be various means. One example involvessimply placing the solution into a container (e.g., a sterile vial) thatalready has air in it in order to incorporate oxygen into theformulation. Another example involves using medical grade air push inorder to place the solution into a container that already has air in it.Yet another example involves using medical grade air push to place boththe solution and air into a container that does not have any air in it.

While this invention has been described in conjunction with the specificembodiments outlined above, it is evident that many alternatives,modifications, and variations will be apparent to those skilled in theart. Accordingly, the preferred embodiments of the invention as setforth above are intended to be illustrative, not limiting. A variety ofmodifications to the embodiments described will be apparent to thoseskilled in the art from the disclosure provided herein. Thus, thepresent invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Variouschanges may be made without departing from the spirit and scope of theinventions as defined in the following claims.

Exemplary Embodiments

A first formulation for stabilizing a radiopharmaceutical, the firstformulation including: a radiopharmaceutical, or a pharmaceuticallyacceptable salt thereof; a gas comprising oxygen; a stabilizer; and asolvent.

The first formulation, where water is the solvent.

The first formulation, where the stabilizer is an excipient compatiblefor human injection.

The first formulation, where the oxygen is present in the gas in anamount of at least about 10 vol. % by total volume of gas.

The first formulation, where the oxygen is present in an amount of about10 vol. % to about 30 vol. % by total volume of gas.

The first formulation, where the oxygen is present in the gas in anamount of about 20.95 vol. % by total volume of gas.

The first formulation, further including an alcohol.

The first formulation, where the alcohol is ethanol.

The first formulation, where the ethanol is present in an amount ofabout 1.0 vol. % to about 10.0 vol. % per total volume of liquid.

The first formulation, wherein the ethanol is present in an amount ofabout 8.0 vol. % per total volume of liquid.

The first formulation, further including an inorganic salt.

The first formulation, where the inorganic salt is a phosphate.

The first formulation, where the aqueous phosphate solution is presentin an amount of about 92 vol. % per total volume of liquid.

The first formulation, where the phosphate is about 21 mM sodiumphosphate with a pH in a rage of 4.0 to 7.0.

The first formulation, where the radiopharmaceutical is [F-18]-FLT.

The first formulation, where the radiopharmaceutical is present in anamount of about 10.00 mCi/mL to about 1000.00 mCi/mL.

The first formulation, where the radiopharmaceutical is present in anamount of about 60 mCi/mL to about 200 mCi/mL.

The first formulation, where the stabilizer is maleic acid.

The first formulation, where the maleic acid is present in an amount ofabout 1 mg/10 mL.

The first formulation, further including sodium phosphate and about0.01% maleic acid in grams of maleic acid per total volume of liquid inmilliliters, where radiopharmaceutical is [F-18]-FLT.

A first apparatus for stabilizing a radiopharmaceutical, the firstapparatus including a container with a formulation having aradiopharmaceutical (or a pharmaceutically acceptable salt thereof), agas comprising oxygen, a stabilizer, and water.

The first apparatus, where the formulation comprises an aqueoussolution.

The first apparatus, where the container is a vial.

The first apparatus, where the container is a syringe.

The first apparatus, where the container is sealable and when sealed, issubstantially impervious to oxygen.

The first apparatus, further including a headspace between a boundary ofthe formula and a boundary of the container, wherein the headspace issubstantially filled with the oxygen.

The first apparatus, where the formula further comprises ethanol.

The first apparatus, where the ethanol is at concentrations of about 1.0vol. % to about 10.0 vol. % per total volume of liquid.

The first apparatus, where the oxygen is present in an amount of about10 vol. % to about 100 vol. % per total volume of gas.

The first apparatus, where the oxygen is present in an amount of about20.95 vol. % per total volume of gas.

The first apparatus, where the ethanol is present in an amount of about8.0 vol. % per total volume of liquid.

The first apparatus, where the formula further comprises aqueousphosphate in an amount of about 92 vol. % per total volume of liquid.

The first apparatus, where the radiopharmaceutical is [F-18]FLT.

The first apparatus, where the radiopharmaceutical is present in anamount of about 10.0 mCi/mL to about 1000.0 mCi/mL.

The first apparatus, where the radiopharmaceutical is present in anamount of about 60.0 mCi/mL to about 200.00 mCi/mL.

The first apparatus, where the stabilizer is maleic acid.

A first method of making a formulation for stabilizing aradiopharmaceutical, the first method including providing aradiopharmaceutical, providing an excipient, providing an aqueoussolution of an alcohol and an inorganic salt, and providing oxygen.

The first method, where an amount of excipient provided is about 0.001to about 100 mg/mL.

The first method, where the excipient is selected from the groupconsisting of maleic acid, beta-cyclodextrin, methylene blue,alpha-cyclodextrin, gentisic acid, cyclohexane dione diamine,thioglycerol, glutathione, tartaric acid, niacinamide, FeCl₃, H₂O₂,glutamic acid, triamine pentaacid, methylene diphosphonic acid,beta-hydroxypropyl cyclodextrin, xanthine, aspartic acid, chlorobutanol,calcium chloride, mannitol, creatanine, calcium gluconate, dimethylacetamide, diazatriazoic acid, sodium succinate, boric acid, sodiumcarbonate, acetic acid, and acetates.

The first method, where the excipient is maleic acid.

A second method of making a formulation for stabilizing aradiopharmaceutical, the second method including: providing a sterilecontainer filled with air; providing a formulation having aradiopharmaceutical (or a pharmaceutically acceptable salt thereof), anstabilizer, and a solvent; and placing the formulation in the sterilecontainer.

The second method, where the formulation is placed in the sterilecontainer by medical grade air push.

The second method, where the solvent is water.

The second method, where the stabilizer is an excipient.

The second method, where an amount of excipient provided is about 0.001to about 100 mg/mL.

The second method, where the excipient is selected from the groupconsisting of maleic acid, fumaric acid, beta-cyclodextrin, methyleneblue, alpha-cyclodextrin, gentisic acid, cyclohexane dione diamine,thioglycerol, glutathione, tartaric acid, niacinamide, FeCl₃, H₂O₂,glutamic acid, triamine pentaacid, methylene diphosphonic acid,beta-hydroxypropyl cyclodextrin, xanthine, aspartic acid, chlorobutanol,calcium chloride, mannitol, creatanine, calcium gluconate, dimethylacetamide, diazatriazoic acid, sodium succinate, boric acid, sodiumcarbonate, acetic acid, and acetates as well as isomers thereof.

The second method, where the excipient is maleic acid.

The second method, where the sterile container is a sterile vial.

The second method, where the sterile container is a sterile syringe.

The second method, where the sterile container is sealable and whensealed, is substantially impervious to oxygen.

A third method of making a formulation for stabilizing aradiopharmaceutical, the method including: providing a sterilecontainer; providing a formulation having a radiopharmaceutical (or apharmaceutically acceptable salt thereof), a stabilizer, and a solvent;and placing the formulation in the sterile container by medical gradeair push.

The third method, where there is no air in the sterile container beforethe formulation is placed in the sterile container.

The third method, where the solvent is water.

The third method, where the stabilizer is an excipient.

The third method, where an amount of excipient provided is about 0.001to about 100 mg/mL.

The third method, where the excipient is selected from the groupconsisting of maleic acid, fumaric acid, beta-cyclodextrin, methyleneblue, alpha-cyclodextrin, gentisic acid, cyclohexane dione diamine,thioglycerol, glutathione, tartaric acid, niacinamide, FeCl₃, H₂O₂,glutamic acid, triamine pentaacid, methylene diphosphonic acid,beta-hydroxypropyl cyclodextrin, xanthine, aspartic acid, chlorobutanol,calcium chloride, mannitol, creatanine, calcium gluconate, dimethylacetamide, diazatriazoic acid, sodium succinate, boric acid, sodiumcarbonate, acetic acid, and acetates.

The third method, where the excipient is maleic acid.

The third method, where the sterile container is a sterile vial.

The third method, where the sterile container is a sterile syringe.

The third method, where the sterile container is sealable and whensealed, is substantially impervious to oxygen.

A first kit including a container with a formulation having aradiopharmaceutical (or a pharmaceutically acceptable salt thereof), agas comprising oxygen, a stabilizer, and a solvent.

The first kit, where the solvent is water.

The first kit, where the formulation comprises an aqueous solution.

The first kit, where the container is a vial.

The first kit, where the container is a syringe.

The first kit, where the container is sealable and when sealed, issubstantially impervious to oxygen.

The first kit, further including a headspace between a boundary of theformula and a boundary of the container, wherein the headspace issubstantially filled with the oxygen.

The first kit, where the formula further comprises ethanol.

The first kit, where the ethanol is at concentrations of about 1.0 vol.%

to about 10.0 vol. % per total volume of liquid.

The first kit, where the oxygen is present in an amount of about vol. %to about 100 vol. % per total volume of gas.

The first kit, where the oxygen is present in an amount of about 20.95vol. % per total volume of gas.

The first kit, where the ethanol is present in an amount of about 8.0vol. % per total volume of liquid.

The first kit, where the formula further comprises aqueous phosphate inan amount of about 92 vol. % per total volume of liquid.

The first kit, where the radiopharmaceutical is [F-18]FLT.

The first kit, where the radiopharmaceutical is present in an amount ofabout 10.0 mCi/mL to about 1000.0 mCi/mL.

The first kit, where the radiopharmaceutical is present in an amount ofabout 60.0 mCi/mL to about 200.00 mCi/mL.

The first kit, where the stabilizer is maleic acid.

What is claimed is:
 1. A method of making a formulation for stabilizinga radiopharmaceutical, the method comprising: providing a F18 labelledradiopharmaceutical, or a pharmaceutically acceptable salt of a F-18labelled radiopharmaceutical thereof in a vial; providing an aqueoussolution of an alcohol and an inorganic salt in the vial; providing agas comprising oxygen in the vial; wherein the oxygen is present in thegas in an amount of at least about 10 vol. % by total volume of gas;providing an excipient in the vial, wherein the excipient is maleicacid.
 2. The method of claim 1; wherein an amount of excipient providedis about 0.001 to about 100 mg/mL.